Investigating the Time-Dependent Reversibility of DCM-Induced Epigenetic, Matrix, and Functional Remodeling

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Project Summary Dilated cardiomyopathy (DCM) is a highly prevalent inherited cardiac disease, characterized by systolic dysfunction, eccentric hypertrophy, and left ventricle dilation. While pharmacologic and mechanical treatments have been shown to partially improve cardiac function, these results are often short lived and highly variable from patient to patient. Moreover, recent studies have demonstrated that epigenetic and matrix dysregulation can persist, even in patients with improved systolic function after treatment. Given that aberrant chromatin remodeling and extracellular matrix (ECM) deposition have been identified as drivers of dilated remodeling—and that chromatin and ECM remodeling can become irreversible over time—it is crucial to understand the time- dependent effects of DCM mutations on reversing maladaptive remodeling at the genome, myocyte, and matrix levels. The central hypothesis of this proposal is that the reversibility of the DCM phenotype is time-dependent due to the accumulation of permanent ECM and chromatin remodeling as the disease progresses. To complete this proposal, I will utilize a DCM mouse model created by the Davis lab which contains a mutation (I61Q) in cardiac troponin C (cTnC) that directly decreases the myofilament’s Ca2+ sensitivity, leading to eccentric hypertrophy, systolic dysfunction, and left ventricle dilation. Importantly, expression of this mutant can be temporally controlled with doxycycline to specifically test our central hypothesis. In this proposal I will 1) Determine the time-dependent effects of I61Q cTnC expression on myocyte, matrix, and chromatin accessibility, 2) Examine the reversibility of DCM remodeling in myocyte, matrix, and chromatin accessibility at different stages of the disease, and 3) Determine if myocytes retain epigenetic memories of the mechanical disequilibrium caused by DCM. Improving our understanding of the time-dependent reversibility of DCM remodeling will better inform therapeutic targets and treatment windows for patients with DCM. Moreover, completion of this project will enhance Bella’s training as an independent scientist and prepare her to one day become a professor in cardiovascular engineering. Receiving the NIH F31 predoctoral fellowship will facilitate important experiments and training that will aid in her pursuit of this career goal. In this project, Bella will gain expertise in multi-omic approaches—such as proteomics, RNAseq, and ATACseq—which are growing in popularity due to their unbiased screening capabilities. The UW Genomics Core will assist Bella in learning how to effectively use these tools, which will not only benefit this project but will also be an incredibly useful skillset for Bella’s future career. Given the clinical relevance of this project, we have engaged Farid Moussavi-Harami, MD, an acting physician- scientist who practices cardiology within the UW Department of Medicine. Dr. Moussavi-Harami’s input as a clinician will be crucial for ensuring our research questions and aims remain relevant to patients, and his mentorship throughout this project will enhance Bella’s training and career development as she aims to eventually run a lab with an emphasis in translational therapeutics and technologies for cardiovascular diseases.